How To Workup and Treat Hypercalcemia (High Yield)

[0:00]Stones, bones, groans, thrones, and psychiatric overtones. Those are the key characteristic symptoms of hypercalcemia that every medical student learns. And what do they stand for? So, stones stands for nephrolithiasis or kidney stones. Bones stands for bone-related complications like osteoporosis and osteitis fibrosis. Groans stands for abdominal pain. Thrones stands for polyuria and constipation, basically meaning you're going to be on the toilet all the time. And then psychiatric overtones describes how patients can present with confusion or even coma, as well as anxiety and depression. If you ever see the combination of polyuria plus constipation together, that is highly specific for hypercalcemia. So if you ever hear that from a patient, you should immediately be thinking about hypercalcemia. In general, these symptoms don't appear until the patient's calcium level is greater than 12 milligrams per deciliter. So usually patients below that level are going to be asymptomatic. Now, let's talk about the workup of hypercalcemia and how you can identify the ideology of patients' hypercalcemia. The most common diagnoses are number one, primary hyperparathyroidism, two, hypercalcemia of malignancy, and three, milk alkali syndrome. So it's kind of interesting with milk alkali syndrome. This actually was very common back in the days when we were using a lot of calcium carbonate to treat peptic ulcer disease. And then it kind of fell off as we started having proton pump inhibitors and other treatments for peptic ulcer disease. But now it's having a resurgence now that we're treating osteoporosis a lot more aggressively and giving a lot more calcium supplements. And one important thing to note is that number one and number two, primary hyperparathyroidism and hypercalcemia of malignancy, are the diagnoses that account for hypercalcemia over 90% of the time. However, you still need to know how to do the workup of hypercalcemia, so you can catch those other 10% of conditions and really make sure you actually nail the diagnosis. So what exactly do we order? Well, the first thing that you need to do is you need to confirm the hypercalcemia. So if you just have a patient come in with a high calcium level, you really need to double-check that it's truly high. You are either going to calculate a corrected calcium value or you're going to check an ionized or free calcium. The reason that we have a correction for calcium is because 45% of calcium is bound to albumin. 50% is free. And then about 5% is bound to anions and phosphates. So if you have a patient that comes in and they have a low albumin, this is falsely going to lower your total calcium level. However, it's not really telling you anything about the amount of free ionized calcium that's out there and being active. And so we actually have a correction factor for the patient's albumin and that's going to be four, which is a normal albumin, minus the patient's albumin. And then multiply that by 0.8 and then add the patient's calcium. So that's how you calculate a corrected calcium. After you've confirmed that the patient has hypercalcemia, then the most important test to check next is the PTH. And that's because the first major branch point in our workup for hypercalcemia is actually checking the PTH and determining is this a PTH dependent process or PTH independent process. All right, so you can see here that I've written that on the left side we have PTH dependent or PTH independent. And so the two lab results that you may get back on the PTH dependent side is going to be a normal PTH or an elevated PTH. Whereas on the PTH independent side, you're going to get a low PTH. So one key thing to note here is that, um, if you have a normal PTH in the setting of hypercalcemia, that is actually abnormal. This is a key thing that comes up in medicine a lot is that sometimes you may see a normal value come back, but it's actually abnormal for it to be within the normal range when you have hypercalcemia. Because if you think about it, PTH is released so that we can increase the amount of calcium in our blood. So if we already have hypercalcemia, your PTH should be completely suppressed. The fact that you still have a normal PTH level, that's actually an incorrect response from the body. So in this case, this normal value is abnormal. And then so on this PTH dependent side, I'm going to split it into a very elevated PTH, and then a normal to minimally elevated PTH. And so if it's a very elevated PTH, you almost certainly can, uh, you know, make the diagnosis of primary hyperparathyroidism. Less common diagnoses you could have here are tertiary hyperparathyroidism when you have a patient with long-standing ESRD and parathyroid carcinoma. On this side, with the normal and minimally elevated PTH, it could still be primary hyperparathyroidism, but it could also be the condition of familial hypocalciuric hypercalcemia, or FHH for short. So if you have this situation, what you're going to want to check next is a 24-hour urine calcium. And if that is greater than 250, that is suggestive of primary hyperparathyroidism. And if it's less than 250, then that is suggestive of familial hypocalciuric hypercalcemia. Moving on to the PTH independent side. So say you've gotten the PTH and you've found that it is adequately suppressed, then what labs are you initially going to order? So the labs you're going to order are PTHrP, 25 hydroxy vitamin D, and 125 hydroxy vitamin D. So if PTHrP is elevated, then you have a diagnosis of hypercalcemia of malignancy, usually from some kind of PTHrP secreting tumor, which is very common in squamous cell cancer and renal cell carcinoma. If the 25 OH vitamin D is elevated, then you have a diagnosis of vitamin D toxicity. And if the 125 hydroxy vitamin D is elevated, then I want you to think of lymphoma and granulomatous diseases. So things like sarcoid, TB, and histoplasmosis. So that's the initial workup for the PTH independent side of things. Get that PTHrP, 25 hydroxy vitamin D, and the 125 hydroxy vitamin D. All right, but if all of that workup is normal or negative, then you're going to go down a slightly different list of differentials and there's kind of four things that we can have here. And that would be lytic bone disease, which is kind of another form of hypercalcemia of malignancy. So especially breast, lung, and multiple myeloma. And then you also could have immobility. So if you see this in like ICU patients who have been intubated for a long time, you can get hypercalcemia of immobility. Medication induced hypercalcemia could be pretty common. So things like thiazides, lithium, vitamin A, and milk alkali are all examples of this. And then you have some rare endocrine things such as hyperthyroidism, which increases your bone turnover, and adrenal insufficiency. So essentially, if your initial pass workup is negative, then you're going to do some additional workup. So for the multiple myeloma, you'll get an SPP, UPP, and serum free light chains. For immobility and medications, you're kind of just going to go off the history. Um, for vitamin A, you can check for vitamin A level. And then for hyperthyroidism, uh, you can check the TSH and you could check a cortisol level if you're suspicious of adrenal insufficiency. So everything that you can order as part of your workup, I've actually put in this kind of pinkish purple color. So first pass, again, you're going to get that PTH to determine if it's PTH dependent or PTH independent. And then if it's PTH dependent, depending on if it's normal or minimally elevated, you may also get a 24-hour urine calcium. But again, a majority of the time, you're just going to be in this primary hyperparathyroid category. For PTH independent, you're going to get PTHrP, 25 hydroxy vitamin D and 125 hydroxy vitamin D. And then if all of that's normal, then you have some additional workup down here to work up these causes. All right, so now let's move on to treatment. And when we're talking about treatment, uh, first we really want to see the degree of hypercalcemia that a patient is experiencing. So, uh, generally, if their hypercalcemia is less than 12, remember that this is considered mild, and most patients are going to be asymptomatic at this range. So they're not going to require treatment. Uh, from 12 to 14, we consider this moderate, and again, immediate treatment is not really needed, unless they're having symptoms. And so if they're having symptoms, you actually treat it in the same way that you would in the severe category. So if they're greater than 14, we consider this severe, and then, uh, we would treat this, uh, ASAP. So treat as soon as possible. I definitely like to include this because a lot of people think, oh gosh, the calcium is 12.5. Like, you know, we got to start treatment right away. But really, if they're not having symptoms, you can kind of defer treatment, encourage the patient to drink some more water and decrease their calcium intake. Whereas if it's greater than 14, that's really when you should start immediate inpatient treatment. So treatment number one is going to be fluids, and this is one of the, you know, hallmarks of treatment. A lot of these patients are going to be extremely volume depleted. So you actually really want to flood them with a lot of fluids. And so they recommend actually doing something like 200 to 300 ccs an hour, and this is going to be the first thing that you want to start right away. The number two thing that you want to start is actually calcitonin. And so calcitonin increases the amount of calcium that you urinate out, but more importantly, it inhibits bone resorption and osteoclast activity. Um, and so this one generally takes four to six hours to work. So onset in four to six hours. But what's really important to know about this one is that it develops something called tachyphylaxis, which means that over time it stops working. For this specific medication, the tachyphylaxis occurs around 48 hours. So after 48 hours, it kind of loses all efficacy. And so that brings us to our number three treatment, which is going to be IV bisphosphonates. And it actually works out really well because the IV bisphosphonates take basically 48 hours to really start having a action. And again, this also helps prevent bone resorption and osteoclast activity. So basically, as that calcitonin is wearing off, that's when your IV bisphosphonate is going to start kicking in. And then it lasts like two to three weeks. So it has a very long duration of action and is really going to help control that hypercalcemia. So if somebody has hypercalcemia of malignancy, you really should be repeating this, uh, basically every four weeks, really to maintain that calcium homeostasis. And the preferred one in all of the literature is going to be zoledronic acid, or Zometa. So preferred equals zoledronic acid. It's been shown to have a high a faster resolution of hypercalcemia, as well as, um, just kind of better outcomes in general. Remember your side effects for bisphosphonates, so that's going to be osteonecrosis of the jaw, atypical femur fractures. And also, you have to be careful in patients with renal insufficiency. So I'm going to write that down here, just caution in renal insufficiency. So what can you use, uh, if somebody has renal insufficiency? Uh, there's actually a very similar acting medication called denosumab. And so this one is going to be a good option if the patient has renal insufficiency, or if they have an allergy to bisphosphonates. One thing that you should know about denosumab is that there is an increased risk for hypocalcemia, so that's something to look out for. Number five is going to be diuretics. Um, and so what we used to actually do was flood these patients with fluids and then diures them at the same time, especially because if you give Lasix, it has a calciuric effect. It starts helping you, uh, eliminate, uh, calcium renally. Uh, but we stopped doing that after the advent of bisphosphonates, because bisphosphonates were just so much more effective. And so there was no need to do the diuretics anymore. Um, so generally, again, the main ones that we start with, like this is the main stay of your therapy. You're going to start them on fluids, calcitonin, and you're going to give them a bisphosphonate right up a front. But if somebody is at risk for volume overload, uh, or if they have heart failure, things like that, uh, basically, that's when you would do fluids plus diuretics. And this is one of the few situations that you would have a patient on both fluids and diuretics at the same time. So if there is CHF or risk for volume overload, but this is definitely not kind of a a standard therapy at at this point in time. And then number six, if somebody's having very refractory hypercalcemia, uh, that's refractory to medical management, then dialysis could be an option. So this would be really your last resort. And then we have some a couple of treatment specific treatments, uh, steroids. So if they have granulomatous disease, steroids actually help, uh, prevent that one alpha hydroxylation of 25 hydroxy vitamin D. So if somebody has sarcoidosis, for example, then steroids is a an indicated treatment for that. And then the last one is that you'll sometimes see a medication called cinacalcet, and this can be used for patients with primary hyperparathyroidism, uh, but it's kind of like a off label use. It's not really like one of our first line medications. All right, and let's just finish off with some bonus pearls. So if a patient has rapid response to fluids, then this should tell you that it's less likely to be malignancy. Calcium level greater than 13, especially on your board exams, is highly correlated to hypercalcemia of malignancy. Because primary hyperparathyroidism rarely gets to this level. So why are kids at higher risk for hypercalcemia from immobility? This is because they have an increased bone turnover. So if they have, um, immobility and say they're in the ICU, they have increased bone turnover compared to an adult, so they would have a higher risk of developing hypercalcemia. Why does calcium cause an AKI or why can't it cause AKI? This is due to vasoconstriction of the afferent atrial. And what is a trick for determining if it's PTH mediated or independent? And this is actually a really interesting one. So this is a chloride to phos ratio of greater than 33. And, uh, this is basically what we used to use before PTH was something that we could test for. Uh, we would check the chloride to phos ratio. Uh, and if it's greater than 33, that would suggest an elevated PTH. Uh, because you can remember PTH as the phosphate trashing hormone. So if PTH is around, it's going to be dumping all your phosphate and you're going to get this elevated ratio. And the one reason that I can find this helpful is because this PTHrP test can sometimes take a really long time to get back. So it can take like two weeks, three weeks sometimes. And so what you can actually do is, uh, if you've determined that their regular PTH is low and you're suspicious for PTHrP being elevated, you can actually use this chloride to phos ratio, uh, to see if there's some kind of PTH mediated process going on. So that's just a very interesting little trick and may come in handy someday for you or you can just impress your attending on rounds. We went over the main symptoms of hypercalcemia, the, you know, approach to working it up and all of the lab tests that you would order, um, depending on whether it's PTH dependent or PTH independent, and then what levels you should be treating, and finally, what some of the main treatments for hypercalcemia are. I hope this video was useful. Thanks again for watching and I'll see you in the next one. Peace.